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Ssd1 and Gcn2 suppress global translation efficiency in replicatively aged yeast while their activation extends lifespan.

eLife | 2018

Translational efficiency correlates with longevity, yet its role in lifespan determination remains unclear. Using ribosome profiling, translation efficiency is globally reduced during replicative aging in budding yeast by at least two mechanisms: Firstly, Ssd1 is induced during aging, sequestering mRNAs to P-bodies. Furthermore, Ssd1 overexpression in young cells reduced translation and extended lifespan, while loss of Ssd1 reduced the translational deficit of old cells and shortened lifespan. Secondly, phosphorylation of eIF2α, mediated by the stress kinase Gcn2, was elevated in old cells, contributing to the global reduction in translation without detectable induction of the downstream Gcn4 transcriptional activator. tRNA overexpression activated Gcn2 in young cells and extended lifespan in a manner dependent on Gcn4. Moreover, overexpression of Gcn4 sufficed to extend lifespan in an autophagy-dependent manner in the absence of changes in global translation, indicating that Gcn4-mediated autophagy induction is the ultimate downstream target of activated Gcn2, to extend lifespan.

Pubmed ID: 30117416 RIS Download

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Associated grants

  • Agency: NCI NIH HHS, United States
    Id: R01 CA207109
  • Agency: NIA NIH HHS, United States
    Id: R01 AG050660
  • Agency: NIH Office of the Director, International
    Id: AG050660
  • Agency: NIH Office of the Director, International
    Id: CA208257
  • Agency: NCI NIH HHS, United States
    Id: R01 CA208257
  • Agency: NCI NIH HHS, United States
    Id: R01 CA095641
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM064475
  • Agency: NIH Office of the Director, International
    Id: CA95641
  • Agency: NIH Office of the Director, International
    Id: CA207109

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